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Introduction
N-Myc downstream-regulated gene 2 (NDRG2) is generally expressed in the brain, heart and muscle (1). Increasing evidence indicates that NDRG2 has specific functions in the regulation of cellular differentiation and tumorigenesis. Indeed, NDRG2 was reported to have a putative role in neural differentiation, synapse formation, and axon survival in response to glucocorticoids, and to participate in the differentiation of monocytes and leukemia cells into dendritic cells (2,3). NDRG2 was discovered as a potential tumor suppressor in meningioma, glioblastoma and melanoma cell lines (4–6). In addition, NDRG2 mRNA and protein are shown to be downregulated in human liver, pancreatic and colon cancer tissues (7,8). Recently, NDRG2 was identified as a potential suppressor of tumor metastasis in highly malignant tumor cells (9,10). NDRG2 inhibited the invasion and migration of highly invasive tumor cells both in vitro and in vivo.
Aggressive cancer progression is initiated by the breakdown of epithelial cell homeostasis which is correlated with the loss of epithelial characteristics and the acquisition of a migratory phenotype such as mesenchymal cells (11). This phenomenon, known as epithelial-mesenchymal transition (EMT), is considered to be a critical event during tumor cell malignancy (11–14). Epithelial cells are connected to each other through specialized structures known as adherens junctions, which are composed of E-cadherin/α- and β-catenin complexes. The development of metastatic carcinoma is accompanied by deregulation of adherens junctions and the decrease of E-cadherin expression is an early step during the initiation of these processes.
Loss of E-cadherin gene expression or E-cadherin protein is frequently found during tumor progression in most types of epithelial cancer. Mutation or inactivation (by DNA methylation) of E-cadherin gene is responsible for such changes. However, in several types of cancer, E-cadherin expression is lost without genomic modifications (15) owing to transcriptional repression of E-cadherin by those EMT-regulating factors (16–20). An increasing number of transcription factors appear to activate EMT in various settings, including Snail (16–18,20,21), Twist (22), high mobility group A2 (HMGA2) (23), Slug (24,25), SIP1 (19) and Ets-1 (26). A central role of these transcriptional regulators is the suppression of the E-cadherin gene. Downregulation of E-cadherin has several important consequences that are of direct relevance to EMT.
Several signaling pathways implicated in the progression of EMT, including the Wnt and phosphoinositide 3-kinase pathways,...